Acne vulgaris is an exceptionally common, recurring disease involving multiple etiological factors including hyperkeratinization, sebaceous gland hyperplasia with seborrhoea, P. acnes proliferation, and inflammation. (See, for example, Thiboutot D. J Invest Dermatol. 2004; 123:1-12; Pawin H et al. Eur J. Dermatol. 2004; 14(1):4-12; and Leyden J J, J Am Acad Dermatol. 2003; 49(3 suppl):S200-S210).
The management of acne can be complex, often requiring aggressive combination therapy and a long-term therapeutic strategy. (See, for example, Thiboutot D. Arch Family Med 2000; 9:179-187; Gollnick H et al, J Am Acad Dermatol. 2003; 49(1 suppl):S1-S37). A recent clinical study investigating the efficacy and safety of adapalene when used concomitantly with oral doxycycline in severe acne subjects showed that the adapalene-doxycycline combination was superior to antibiotic monotherapy, confirming results from previous adapalene-antibiotic combination studies. (See Thiboutot D. et al, Combination therapy with adapalene gel 0.1% and doxycycline for severe acne vulgaris: a multicenter, investigator-blind, randomized, controlled study. Submitted; Wolf J E Jr et al, J Am Acad Dermatol. 2003; 49(3 suppl):S211-S217; Cunliffe W J et al, J Am Acad Dermatol. 2003; 49(3 suppl):S218-S226). Maintenance therapy is necessary for many acne patients, as acne lesions have been shown to return after discontinuing a successful treatment regimen. (See Gollnick H et al, J Am Acad Dermatol. 2003; 49(1 suppl):S1-S37; Thielitz A et al, Br J. Dermatol. 2001; 145:19-27). Despite the variety of medications available for the treatment of acute acne, there are few well-controlled studies providing evidence for prophylactic efficacy.
An effective maintenance therapy should prevent acne recurrence by targeting the early stages of comedogenesis and the precursor of mature acne lesions, the microcomedo. (See Gollnick H et al, J Am Acad Dermatol. 2003; 49(1 suppl):S1-S37; Wolf J E. SKINmed. 2004; 3:23-26). Currently, the most effective comedolytic agents are oral isotretinoin and topical retinoids. (See Cunliffe W J, et al, Br J. Dermatol. 2000; 142:1084-1091). Oral isotretinoin is an impractical choice for long-term therapy due to the potential for toxicity and teratogenicity. Topical anti-acne medication such as retinoids, could be associated with elevated skin irritation, so careful consideration must be given to the tolerability of a potential maintenance therapy. Cutaneous side effects may decrease the likelihood of treatment adherence, particularly when treating an asymptomatic condition. (See Koo J, SKINmed. 2003; 2:229-33; and Haider A et al, JAMA. 2004; 292:726-735).
Recently published guidelines recommend topical retinoids with or without benzoyl peroxide for maintenance following initial combination treatment with an antimicrobial. (See Gollnick H et al, J Am Acad Dermatol. 2003; 49 (1 suppl):S1-S37). Adapalene has demonstrated a more favorable tolerability profile than other topical retinoids when applied as monotherapy. (See Dosik J S et al, Cumulative Irritation Potential of adapalene cream and gel, 0.1% compared to tazarotene cream, 0.05% and 0.1%. Cutis. In press; Dosik J S et al, Cumulative irritation potential of adapalene cream and gel, 0.1% compared to tretinoin micro, 0.04% and tretinoin micro 0.1%. Cutis. In press; Greenspan A et. al., Cutis. 2003; 72:76-81; Haider A et al, JAMA. 2004; 292:726-735; Dunlap F E et al, Br J. Dermatol. 1998; 139:17-22; Caron D et al, J Am Acad Dermatol. 1997; 36: S110-S112; Egan N et al, Cutis. 2001; 68(suppl 4):20-24; Brand B et al, J Am Acad Dermatol. 2003 September; 49(3 Suppl):S227-S232; Caron D et al, J Am Acad Dermatol. 1997; 36: S113-S115)
Acne is a chronic and relapsing disease (Kraning K K, Odland G F. Prevalence, morbidity, and cost of dermatological diseases. J Invest Dermatol. 1979; 73: Suppl:395-401). It has been shown that up to 21% of the patients treated with isotretinoin, which is considered today as the best acne treatment, can relapse (Wessels F, Anderson A N, Kropman K. The cost-effectiveness of isotretinoin in the treatment of acne. S African Med J. 1999; 89:780-784). Maintenance therapy is then necessary for many acne patients, as acne lesions have been shown to return after discontinuing a successful treatment regimen (Gollnick H, Cunliffe W, Berson D, et al. Management of acne. A report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003; 49(1 suppl):S1-S37 and Thielitz A, Helmdach M, Ropke E-M, Gollnick H. Lipid analysis of follicular casts from cyanoacrylate strips as a new method for studying therapeutic effects of antiacne agents. Br J. Dermatol. 2001; 145:19-27. Hypercornification is an early feature of acne which results in ductal hyperproliferation and usually precedes inflammation; if it is associated with suboptimal therapy, it can result in microcomedone proliferation (Cunliffe W J, Holland D B, Clark S M, Stables G I. Comedogenesis: some aetiological, clinical and therapeutic strategies. Dermatology 2003; 206(1):11-6. Normalizing follicular desquamation is then the key to achieve and maintain control of acne. Today it is established that retinoids such as Adapalene aid the differentiation and reduction of keratinocytes (Gollnick H. Current concepts of the pathogenesis of acne: implications for drug treatment. Drugs 2003; 63(15):1579-96). A recent study showed that the application of Adapalene gel, 0.1% significantly helps to control the microcomedone count during a 12-week maintenance treatment after a previous combination therapy (Thielitz A, Sidou F, Gollnick H. Control of microcomedone formation throughout a maintenance treatment with adapalene gel, 0.1%. J. Eur Acad Dermatol Venereol. 2007 Jul.; 21(6):747-53). These results have been further confirmed in two maintenance studies (Thiboutot D, Shalita A, Yamauchi P et al. Adapalene gel, 0.1% as a maintenance therapy after a combined treatment with doxycycline. Arch Dermatol. 2006 May; 142(5):597-602 and Alirezai M, George S A, Coutts I, Roseeuw D I, Hachem J P et al. Daily treatment with adapalene gel 0.1% maintains initial improvement of acne vulgaris previously treated with oral lymecycline. Eur J. Dermatol. 2007 Jan.-Feb.; 17(1):45-51).
Current guidelines recommend early initiation of combination therapy with topical retinoids and antimicrobials for all but the most severe cases of acne, followed by topical retinoid maintenance therapy with or without benzoyl peroxide (BPO). This approach has the added benefit of reducing the exposure to long-term antibiotic use and minimizing the risk of antibiotic resistance.
Recently, a unique fixed-dose combination, Adapalene BPO Gel, has been granted with Marketing Authorization in Europe under the tradename of Epiduo® (Galderma). Adapalene BPO Gel is a unique antibiotic-free combination of Adapalene 0.1%, a well-tolerated and efficacious topical retinoid, and BPO 2.5%, a well established antimicrobial agent. The complementary modes of action, efficacy and safety profiles of these two agents make Adapalene BPO Gel the most appropriate choice for once-daily treatment for all types of acne but the most severe. Adapalene possesses anticomedogenic, comedolytic, and anti-inflammatory properties (Gollnick H, Schramm M. Topical drug treatment in acne. Dermatology. 1998; 196:119-125; Brogden R N, Goa K L. Adapalene: a review of its pharmacological properties and clinical potential in the management of mild to moderate acne. Drugs. 1997; 53:511-519; Waugh J, Noble S, Scott L J. Adapalene: a review of its use in the treatment of acne vulgaris. Drugs. 2004; 64:1465-1478)
Efficacy and safety of Adapalene BPO Gel has been established in a large clinical program (Andres P, Pernin C, Poncet M. Adapalene-benzoyl peroxide, a new fixed dose combination for the treatment of acne vulgaris: a randomized, bilateral (split-face), dose-assessment study of cutaneous tolerability in healthy subjects. Cutis. 2008; 81:278-284; Thiboutot D M, Weiss J, Bucko A, et al. Adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol. 2007; 57(5):791-799).
When applied for 3 months, Adapalene BPO Gel combination provides significantly greater efficacy for the treatment of moderate acne vulgaris and a quicker onset of action relative to respective monotherapies, with a comparable safety and tolerability profile relative to Adapalene.
A 12-month continuous-use study is of particular interest in the frame of maintenance treatment. This study supports the safe and effective use of Adapalene BPO Gel for up to 12 months alone (Pariser D M, Westmoreland P, Morris A, Gold M H, Liu Y, Graeber M. Long-term safety and efficacy of a unique fixed-dose combination gel of adapalene 0.1% and benzoyl peroxide 2.5% for the treatment of acne vulgaris. J Drugs Dermatol. 2007; 6(9):899-905.
Clinically significant Inflammatory and Non-Inflammatory Lesion count reductions were observed as early as week 1 and, most importantly, continued to increase after the first 3 months of treatment to reach 70% and 76% respectively, after 1 year. Eighty percent (80%) of subjects reported moderate, marked, or complete improvement of their acne at study end.
If not appropriately treated, acne may cause serious physical and emotional scarring and can significantly impact the quality of life of those affected by the disease. Because long term treatment with antibiotics is no longer wished, it is therefore the objective of this invention to provide a novel therapy regimen for the treatment of acne related diseases, which do not induce antibiotic resistance, and is safe and effective when used for a maintenance therapy.